This proposal outlines experiments to explore the synthesis, structure, and reactivity of two novel naturally occurring alkaloid types. The long term goal in each case is to understand their chemistry and to provide the tools necessary to probe their biochemical functions in detail. In 1998, studies began on the diazonamide family of marine cytotoxins. The work has advanced such that a detailed examination of their structure / activity relationships is now possible. Methods to further streamline construction of diazonamide polyhetereocycles are proposed as are selected modifications to facilitate additional research into their antimitotic effects on animal cell culture. The diazonamide diarylaminal core is synthesized via an oxidationinitiated cyclization event and this theme is also present in studies proposed for palau'amine and its relatives. The context surrounding palau'amine is similar to that observed for diazonamides several years ago. The molecule is a new structural type that has proven especially difficult to replicate in the laboratory. It is potently immunosuppressive in vitro and shows broad-based antimicrobial activity. However, there is neither information to suggest a mode of action nor a supply of compound to fuel further research. A strategy to synthesize the palau'amine bis-guanidine array via oxidative spiroannulation is outlined. The chemistry operates on a dimeric substrate whose symmetric and non-symmetric forms give rise to diastereomeric products. The choice of substrate dictates whether the pathway will lead to palau'amine or one of its diastereomeric relatives. In this way, it is possible to navigate the problem in a divergent manner - wherein one core reaction sequence branches out to reach to larger family of products. Nature seems to produce this structural type similarly. However, the synthetic approach gives access to non-natural congeners invaluable for probing their effects on microbes and T-cells in molecular detail. [unreadable] [unreadable]